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X-ray crystal structures of Enterococcus faecalis thymidylate synthase with folate binding site inhibitors. | LitMetric

AI Article Synopsis

  • - Enterococcus faecalis (Ef) infections are a significant health concern, leading researchers to focus on Thymidylate synthase (TS) as a potential target for new antibacterial treatments.
  • - Previous studies revealed the crystal structure of EfTS with a specific metabolite, indicating its role as a metabolite reservoir, although the interaction with inhibitors was not fully explored.
  • - The current research identified phthalimidic core inhibitors and successfully determined two new X-ray crystallographic structures of EfTS with various inhibitors, supporting its function in the folate system and laying the groundwork for future drug design.

Article Abstract

Infections caused by Enterococcus faecalis (Ef) represent nowadays a relevant health problem. We selected Thymidylate synthase (TS) from this organism as a potential specific target for antibacterial therapy. We have previously demonstrated that species-specific inhibition of the protein can be achieved despite the relatively high structural similarity among bacterial TSs and human TS. We had previously obtained the EfTS crystal structure of the protein in complex with the metabolite 5-formyl-tetrahydrofolate (5-FTHF) suggesting the protein role as metabolite reservoir; however, protein-inhibitors complexes were still missing. In the present work we identified some inhibitors bearing the phthalimidic core from our in-house library and we performed crystallographic screening towards EfTS. We obtained two X-ray crystallographic structures: the first with a weak phthalimidic inhibitor bound in one subunit and 5-hydroxymethylene-6-hydrofolic acid (5-HMHF) in the other subunit; a second X-ray structure complex with methotrexate. The structural information achieved confirm the role of EfTS as an enzyme involved in the folate pool system and provide a structural basis for structure-based drug design.

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Source
http://dx.doi.org/10.1016/j.ejmech.2016.07.066DOI Listing

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